1. Field of the Invention
This invention relates to neurobiology, neurology and pharmacology. More particularly, it relates to methods for promoting survival of cells of the nervous system using Death Receptor-6 (DR6) antagonists, optionally in combination with p75 antagonists. The invention also relates to methods of treating neurodegenerative conditions by the administration of a DR6 antagonist, optionally in combination with a p75 antagonist. The invention also relates to methods of preventing the interaction of DR6 and p75 using DR6 and/or p75 antagonists.
2. Background
Apoptosis (i.e. programmed cell death) has been shown to play an important role in numerous diseases of the nervous system including both acute and chronic injuries. For example, the role of apoptosis has been demonstrated in Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neuron disease (e.g. amyotrophic lateral sclerosis, which is also called ALS or Lou Gehrig's disease), multiple sclerosis, neuronal trauma and cerebral ischemia (e.g. stroke).
Many studies have been directed to understanding the molecular mechanisms of apoptosis, and these studies have led to the discovery of a family of receptors called the death receptors. Eight death receptors, which are characterized by a cytoplasmic death domain, have been identified thus far. The death receptors have been grouped into two different families. Members of the first family recruit a death inducing signaling complex (DISC), which promotes apoptotic signaling. Members of the second family recruit a different set of molecules to transduce apoptotic signals. Interestingly, members of the second family also transduce cell survival signals.
Death receptor 6 (DR6) is a member of the second family of death receptors. DR6 is widely expressed, but appears to function differently in different cell types. DR6 mRNA has been observed in heart, brain, placental, pancreas, lymph node, thymus and prostate tissues. Lower levels have been observed in other cell types including skeletal muscle, kidney and testes, but little or no expression has previously been observed in adult liver or any lines of hematopoeitic origin. Interestingly, it has been observed that DR6 is capable of inducing apoptosis in only a subset of cells tested. For example, overexpression of DR6 in HeLa S3 cervical carcinoma cells resulted in apoptosis in a death-domain-dependent manner (Pan et al. FEBS 431:351-356 (1998)). In addition, Nikoleav et al. (Nature 457:981-990 (2009)) have shown that beta-amyloid precursor protein (APP) is a DR6 ligand and suggested that the binding of an APP fragment to DR6 triggers degeneration of neuronal cell bodies and axons. In contrast, DR6 did not induce cell death in MCF7 (a human breast adenocarcinoma line) cells (Pan et al. FEBS 431:351-356 (1998)). The characteristics that differentiate a cell's response to DR6 expression and signaling have not yet been identified.
Drugs that can specifically modulate apoptosis may be useful for treating diseases involving neuronal cell death, for example, because neurons may have less capacity to regenerate than other cell types. However, currently available anti-apoptotic drugs have low specificity and selectivity and as a result, produce undesirable side effects. Such side effects might be reduced or avoided by for example, targeting anti-apoptotic drugs specifically to the desired site of action. Alternatively, characterization of death receptors such as DR6 that specifically act in a particular subset of cell types has the potential to provide a more specific therapeutic effect.